孟鲁司特对大鼠一氧化碳中毒迟发性脑病的防治作用

The prophylactic and therapeutic effects of montelukast on delayed neuropsychologic sequelae after acute carbon monoxide poisoning in rat model

目的研究半胱氨酰白三烯受体．1（cysteinylleukotrienereceptor．1，CysLTlR）拮抗剂孟鲁司特（montelukast）对一氧化碳（carbonmonoxide，CO）中毒大鼠迟发性脑病（delayedneuropsychologicalsequelae，DNS）的防治作用，探讨其发挥作用的可能机制。方法将90只大鼠适应性饲养一周，行Morris水迷宫淘汰不合格大鼠，随机（随机数字法）抽取10只作为对照组（Con组），剩余大鼠采用改良腹腔注射CO气体法建立急性CO中毒模型，将染毒后存活大鼠随机（随机数字法）分为CO中毒组（Mod组）、孟鲁司特低剂量组（ML组）、孟鲁司特中剂量组（MM组）、孟鲁司特高剂量组（MH组），每组10只。各组采用灌胃法给药，染毒后30min、4h、12h各给药1次，后每隔12h给药1次，连续给药7d。同期对照组给予等容积的生理盐水。染毒后第21天行Morris水迷宫测定平均逃避潜伏期，筛选DNS大鼠，采用HE染色观察皮层及海马CAl区病理学变化，TUNEL法观察皮层及海马CAl区神经细胞凋亡。结果CO染毒各组大鼠出现认知功能下降，逃避潜伏期（S）在Mod组（43．3±15．5）、ML组（31．5±13．2）和MH组（30．1±12．2）较Con组（12．1±3．0）明显延长（P〈0．05），但MM组（15．0±6．6）与Con组相比，差异无统计学意义（P〉0．05）。与Mod组相比，孟鲁司特各组较Mod组逃避潜伏期缩短，但仅MM组差异有统计学意义（P〈0．05）。Con组大鼠未发生DNS，染毒各组大鼠均有发生DNS，其中Mod组、ML组、MM组、MH组分别有8只、5只、1只、4只大鼠发生DNS，其中Mod、ML、MH组与Con组相比差异有统计学意义（P〈0．05）；MM组大鼠DNS发生率低于Mod组，差异有统计学意义（P〈0．05）；Mod组脑组织病理损害严重、神经细胞凋亡增多，而孟鲁司特各组脑组织病理损伤减轻、神经细胞凋亡减少，均以MM组病理损伤及细胞凋亡减轻最明显。结论孟鲁司特可改善大鼠认知功能，降低DNS发病率，减少神经细胞凋亡，减轻神经细胞病理损伤，对CO中毒DNS大鼠有一定保护作用。

Objective o investigate the prophylactic and therapeutic effects of montelukast, a cysteinyl leukotriene receptor-1 （CysLT1 R） antagonist, on the delayed neuropsychological sequelae （DNS） in rat model of carbon monoxide （CO） poisoning and to explore the possible underlying mechanism. Methods A total of 90 rats were acclimated for one week prior to screening rat by .Morris water maze test. Ten rats were randomly assigned to control group （ Con group） , and the remaining 80 rats were subjected to modified method of intraperitoneal injection of CO gas to establish animal model of acute CO poisoning, Thereafter, the survival rats randomized into CO poisoning group （ Mod group） , low-dose montelukast group（ MI, group）, medium-dose montelukast group （ MM group）, high-dose montelukast group （ MH group） （ n = 10 each）. Montelukast was accordingly administered via intragastric tube at different intervals （30 rain, 4 h and 12 h） after CO poisoning, and then montelukast was administered every 12 hours tor 7 consecutive days. The rats of control group and Mod group received equal volume of normal saline instead at given intervals. Twenty-one clays after CO exposure, the average escape latency was measured by Mort＇is water maze test to screen DNS rats followed by H-E staining to observe the pathological changes of cortex and hippocampal CA1 region and TUNEL was used to assess the apoptosis of neurons in cortex and hippocampal CA1 region after rats sacrificed. Results All CO-exposed rats exhibited cognition function lowered, and the escape latency （seconds） in Mod group （43.3 ± 15.5）, ML group （31.5 ± 13.2） and MH groups （30. 1±12.2） was significantly prolonged compared with Con group （12. 1 ± 3.0） （P 〈 0.05）, whereas the difference between MM group （ 15.0± 6.6） and Con group was statistically insignificant （P 〉 0.05）. Compared with Mod group, the escape latency in montelukast treatment groups was shortened, whereas the significant diftrence in escape latency only found between Mod group and MM group （P 〈 0. 05）. Except for Con group, DNS was evident in CO-exposed groups, and the numbers of DNS rats in Mod, ML, MM and MH groups were 8, 5, 1, 4, respectively, which made statistically significant diftrences to Con group （P 〈 0. 05） except MM group. The DNS incidence in MM group was lower than that in Mod group （P 〈 0. 05）. Mod group exhibited severe histopathological injm7 to the brain, with evident apoptosis of neural cells, whereas in the groups with montelukast treatment, histopathological damage to the brain was mitigated and the number of apoptotic neuronal cells was diminished noticeably in MM group. Conclusion Montelukast can ameliorate the cognitive function of rats, decrease the incidence of DNS aml reduce the apoptosis of neural cells as well as attenuate neuronal cell injury, thus exerting neoroprotection against DNS in rats with CO poisoning.